US11524014B2 - Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor with sustained multi-phasic release profiles and methods of use - Google Patents

Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor with sustained multi-phasic release profiles and methods of use Download PDF

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US11524014B2
US11524014B2 US17/437,525 US202017437525A US11524014B2 US 11524014 B2 US11524014 B2 US 11524014B2 US 202017437525 A US202017437525 A US 202017437525A US 11524014 B2 US11524014 B2 US 11524014B2
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breast
patient
aromatase inhibitor
pharmaceutical formulation
concentration
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Stephen Nigel Birrell
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Havah Therapeutics Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • Testosterone is critical in the regulation of immune function in both men and women (Gubbels Bupp, 2018). There are several physiological and disease states where it is desirable to increase the tissue level of 5 alpha dihydrotestosterone (DHT) while at the same time reducing oestradiol level within the same tissue without causing significant perturbations in serum oestradiol levels.
  • DHT is predominantly an intra-tissue hormone derived from testosterone which is delivered to that tissue via the circulation. Delivery of testosterone to the tissue which requires treatment in women is problematic due to the relatively small therapeutic window available to dose with testosterone without causing androgenic side-effects.
  • breast pain and its treatment Another problem in the prior art is breast pain and its treatment.
  • Breast pain is a significant problem in female health. It has been estimated that 45% of woman in their thirties indicated that breast pain impinges on their quality of life, and 10% indicated that they had experienced breast pain for at least half their life.
  • tamoxifen and aromatase inhibitors have been used as an off-label medication for this condition.
  • tamoxifen is associated with significant side effects that impact on its compliance in patients, and aromatase inhibitors have been contraindicated in pre-menopausal women as a single agent due to resultant perturbations in the hypothalamic-pituitary-ovarian axis.
  • aromatase inhibitors have been contraindicated in pre-menopausal women as a single agent due to resultant perturbations in the hypothalamic-pituitary-ovarian axis.
  • the elasticity of breast tissue is recognized as a factor in the formation of breast cancer. It has been demonstrated that increased elasticity in breast cells results in an increased mechano-transduction across the genome of a cell, which may result in greater malignant transformation. There is a need in the art for compositions that provide pharmaceutical formulations that decreases mechano-transduction on the genome of a cell to reduce the risk of malignant transformation.
  • a further problem in the art is that of tissue specific autoimmune inflammatory conditions, particularly those presenting in the breast. These conditions may be termed Autoimmune Inflammatory Mastitis (AIM).
  • AIM Autoimmune Inflammatory Mastitis
  • the anatomical, histological, and physiological roles of salivary glands and mammary glands are similar as they both belong to the effector sites of the associated mucosal immune system leaving them vulnerable to autoimmunity.
  • Autoimmune breast tissue compared to normal breast tissue, has been demonstrated to have elevated aromatase (that converts androgens to estradiol) and other factors associated with inflammation, such as IGF2, EGFR, TGF- ⁇ , PDGFR- ⁇ and ⁇ , which have been found to be upregulated.
  • AIM is usually treated with heavy immunosuppressive therapy and/or disfiguring surgery and there is therefore a need for an improved therapy.
  • pharmacokinetics is a description of the rate and extent of uptake, distribution and/or elimination of drugs in the body.
  • pharmacodynamics is a description of how drugs affect the body or a portion of the body.
  • Drug compositions may have different pharmacokinetics and/or pharmacodynamics profiles. For example, some drug compositions may have zero order, first order, or second order kinetics.
  • the kinetics and/or dynamics may have an impact on the efficacy of a drug composition and/or the efficacy of the on treatment.
  • the role that pharmacokinetics and/or pharmacodynamics plays in certain drug compositions, or certain drug delivery systems may be relevant to a particular drug, drug composition, and/or outcome for a subject.
  • the present disclosure in one or more embodiments is directed to addressing and/or ameliorating one or more of the disadvantages of the prior art, or to at least provide a useful pharmaceutical formulation or therapeutic delivery system, as will become apparent from the disclosure herein.
  • the present disclosure in one or more embodiments may also provide other advantages and/or improvements as discussed herein.
  • a delivery system which delivers testosterone and aromatase inhibitor in a multi-phasic release pattern.
  • a pharmaceutical formulation described herein there may be provided an early peak of serum testosterone, which is rapidly blocked by a high level of aromatase inhibitor allowing the induction of 5 alpha reductase conversion of testosterone to DHT.
  • the formulation may then provide for a rapid reduction of the aromatase inhibitor to ensure that there is not a blockade globally of oestradiol production and symptomatic lowering of oestradiol level in the serum.
  • a pharmaceutical formulation comprising: an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor and a binding agent; the formulation upon administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor; and the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • a pharmaceutical formulation comprising: an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor and a binding agent; the formulation upon administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor, and the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • a pharmaceutical formulation comprising: an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor and a binding agent; the pharmaceutical formulation is compressed into a pellet; the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor; and the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • a pharmaceutical formulation comprising: an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor and a binding agent; the pharmaceutical formulation is compressed into a pellet; the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor; and the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • the pharmaceutical formulation comprises: 60 mg to 120 mg of a testosterone, or an ester thereof, 2 mg to 6 mg of an aromatase inhibitor, more preferably 4 mg to 6 mg of an aromatase inhibitor, and stearic acid; the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.25 mm to 4.75 mm and a length of between 4 mm to 7 mm; the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the aromatase inhibitor, and the sustained release multi-phasic concentration pattern comprises:
  • the testosterone or an ester thereof has initially a decreasing serum level concentration and then an increasing serum level concentration and the aromatase inhibitor has its Tmax concentration in the plasma.
  • the pharmaceutical formulation comprises: 60 mg to 120 mg of a testosterone, or an ester thereof, 2 mg to 6 mg of an aromatase inhibitor, more preferably 4 mg to 6 mg of an aromatase inhibitor, and stearic acid; the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.25 mm to 4.75 mm and a length of between 4 mm to 7 mm; the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the aromatase inhibitor, and the sustained release multi-phasic concentration pattern comprises:
  • Tmax first peak in concentration
  • the aromatase inhibitor in the pharmaceutical formulation during the first time period does not exhibit zero-order release.
  • the aromatase inhibitor exhibits first order release.
  • the aromatase inhibitor in the pharmaceutical formulation during the second time period does not exhibit zero order release.
  • the androgenic agent e.g., testosterone or an ester thereof
  • the androgenic agent does not exhibit zero order release.
  • the aromatase inhibitor in the pharmaceutical during the third time period does not exhibit zero order release.
  • the androgenic agent in the pharmaceutical formulation during the third time period does not exhibit zero order release.
  • the aromatase inhibitor exhibits first order release.
  • the androgenic agent in the pharmaceutical formulation during the third time period, exhibits first order release.
  • the aromatase inhibitor in the pharmaceutical formulation during the fourth time period does not exhibit zero order release.
  • the androgenic agent in the pharmaceutical formulation during the fourth time period does not exhibit zero order release.
  • the aromatase inhibitor exhibits first order release.
  • the androgenic agent in the pharmaceutical formulation during the fourth time period, exhibits first order release.
  • the first time period ends right after the androgen has a first peak in concentration (Tmax) in the serum. In certain exemplary embodiments of the pharmaceutical formulation the first time period ends between 5 hours to 14 hours. In certain exemplary embodiments of the pharmaceutical formulation the first time period ends between 5.5 hours to 13 hours.
  • the second time period ends right after the aromatase inhibitor has its Tmax. In certain exemplary embodiments of the pharmaceutical formulation the second time period ends between 23 hours to 80 hours.
  • certain embodiments are directed to a pharmaceutical formulation
  • a pharmaceutical formulation comprising: approximately 80 mg of a testosterone or an ester thereof, approximately 4 mg anastrozole and approximately 2 mg of a stearic acid; the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.4 mm to 4.6 mm and a length of between 4 mm to 7 mm; the pellet upon subcutaneously administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the anastrozole; the sustained release multi-phasic concentration pattern comprising: a first time period of in which the testosterone or an ester thereof, has a first peak in concentration (Tmax) in the serum and the anastrozole is increasing in concentration in the plasma but is below its Tmax concentration in the plasma; a second time period in which the testosterone or an ester thereof, has initially a decreasing serum level concentration and then an increasing serum level concentration and the anastrozole has its Tmax concentration
  • a pharmaceutical formulation comprising: an effective amount of an androgenic agent an effective amount of an aromatase inhibitor and a binding agent; the pharmaceutical formulation is compressed into a pellet; the pellet upon subcutaneously administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor; and the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising: a first time period in which the androgenic agent has a first peak in concentration (Tmax) in the serum and the aromatase inhibitor does not have its Tmax concentration in the plasma; a second time period in which the androgenic agent has a decreasing serum level concentration and then an increasing serum level concentration and the aromatase inhibitor has its Tmax concentration in the plasma; a third time period in which the androgenic agent has a second peak concentration in the serum that is less than its Tmax and the aromatase inhibitor is gradually decreasing in concentration in
  • FIG. 1 For example, adrenal gland and/or ovary gland.
  • further embodiments are directed to the prophylaxis or treatment of autoimmune inflammatory mastitis in a patient in need thereof.
  • a method for the prophylaxis or treatment of autoimmune inflammatory mastitis in a patient in need thereof comprising administering to the patient 1) an effective amount of an androgenic agent and 2) an effective amount of an aromatase inhibitor.
  • the androgenic agent and the aromatase inhibitor may be administered to the patient in the same pharmaceutical formulation or in separate formulations to one another. Accordingly, the present disclosure extends to all combination treatments of the patient for autoimmune inflammatory mastitis.
  • combination treatment is meant the androgenic agent and the aromatase inhibitor may be administered together at the same time or sequentially one after the other by the same or different routes whereby the androgenic agent and the aromatase inhibitor exert their respective therapeutic effect in overlapping therapeutic windows, as may be determined by a medical physician or attendant.
  • the androgenic agent and the aromatase inhibitor are administered in the same or in different sustained-release pharmaceutical formulations.
  • the sustained release pharmaceutical formulation(s) are for subcutaneous delivery of the androgenic agent and the aromatase inhibitor to the patient, e.g., in solid-dosage form(s) such as in the form of pellet(s).
  • the androgenic agent and the aromatase inhibitor are provided in the same sustained-release pharmaceutical formulation.
  • the sustained-release formulation can, for example, be a pharmaceutical formulation as described herein for providing a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor.
  • further embodiments are directed the use of a pharmaceutical formulation in methods of treating autoimmune inflammatory mastitis to a patient in need thereof, comprising administering the pharmaceutical formulation to the patient in the form of a subcutaneous pellet comprising: i) an effective amount of an androgenic agent; and ii) an effective amount of an aromatase inhibitor.
  • the autoimmune inflammatory mastitis for which the patient is treated in accordance with the present disclosure may, for example, be selected from the group consisting of idiopathic inflammatory macromastia, plasma cell mastitis, granulomatous mastitis, and combinations of the foregoing.
  • the present invention further extends to the use of an androgenic agent in the manufacture of a medicament for the prophylaxis or treatment of autoimmune inflammatory mastitis in a patient in need thereof in combination with an effective amount of an aromatase inhibitor.
  • an aromatase inhibitor in the manufacture of a medicament for the prophylaxis or treatment of autoimmune inflammatory mastitis in a patient in need thereof in combination with an effective amount of an androgenic agent.
  • the androgenic agent administered or included in a pharmaceutical formulation for use in the treatment of autoimmune inflammatory mastitis (AIM) or an AIM condition as described herein is a testosterone, or a pharmaceutically acceptable salt or an ester thereof.
  • the aromatase inhibitor may also be utilised in the form of a pharmaceutically acceptable salt or an ester thereof.
  • AABD absolute area of breast density
  • an androgenic agent means an agent that increases androgenic activity and/or synthesis.
  • an androgenic agent may be a steroid hormone that binds with high affinity (in the pM or nM range) and specificity to its intracellular mediator, the androgen receptor resulting in receptor conformational change allowing cofactor inclusion, nuclear transportation and/or stimulation of transactivation activity.
  • the androgenic agent may, for example, be an androgen such as an androgen selected from the group consisting of: testosterone, methyltestosterone, and dehydroepiandrosterone. Combinations of these androgenic agents may also be contemplated.
  • esters may include but are not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate and/or isocaproate esters.
  • area breast density percentage means the proportion or percentage of fibro-glandular (dense) tissue relative to the total surface area of the breast on a mammogram. For example, this may be measured using CUMULUS software algorithms or visual inspection of a mammogram. Several other tests that may be used to measure ABD %, including but not limited to, VOLPARA, QUANTRA, and methods taking into account the surface area of fibro-glandular tissue in a mammogram.
  • aromatase inhibitor means a chemical compound, hormone or polypeptide that blocks and/or inhibits the activity of aromatase, which is an enzyme that converts androgens to estrogens.
  • the aromatase inhibitor may, for example, be selected from the group consisting of: anastrozole, exemestane, and letrozole.
  • autoimmune inflammatory mastitis means a condition in which non-infective, non-lactational inflammation of breast tissue occurs as the result of autoimmune reaction to elements within the breast tissue.
  • breast cancer means a malignant proliferation of epithelial cells lining the ducts or lobules of the breast.
  • breast elasticity means a measurement of the pressure required to achieve a given fractional deformation of the breast or a part of the breast.
  • Another example may be to directly measure the elasticity of breast tissue by applying shear waves through the breast tissue, for example, using the SuperSonic Imagine AixplorerTM that uses SuperSonic Imagine's ShearWaveTM Elastography.
  • breast stiffness means, in its broadest sense, as the measurement of the resistance of a breast to deformation. Factors that may influence the degree of breast stiffness include but is not limited to, physical forces generated by interactions between cells and between cells and the extracellular matrix, the number of cells and the extent of collagen present in the breast, the degree of fluid retention within the breast, the degree of proteoglycan expression and/or combinations thereof.
  • One example of measuring breast stiffness includes the use of the formula force/deformation (dN/cm), where dN denotes deca-Newtons and cm centimetres, wherein the deformation may be determined as the difference between the radius of the mammographic area semicircle and the radius of the volumetric hemisphere, and the compression force is recorded from the mammogram, such as a digital mammogram.
  • the deformation may be determined as the difference R1 ⁇ R2, where R1 is the un-compressed radius, and R2 is the compressed radius.
  • breast tissue means the collection of epithelial cells, stromal cells, extracellular matrix, and/or migratory cells, located within and/or in the vicinity of the breast.
  • an agent or compound means a sufficient amount of the agent or compound to provide the desired therapeutic effect and is nontoxic, has an acceptable nontoxic profile and/or an acceptable side effects profile.
  • the amount required may vary from patient to patient, depending, for example, on age, the general condition of the patient, the severity of the condition being treated, the particular agent or compound administered, and/or one or more combinations of these factors.
  • An appropriate “effective amount” typically in an individual case may be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or using routine experimentation.
  • MBD mammographic breast density
  • FGT fibro-glandular tissue
  • the absolute amount of FGT may be either estimated as a function of surface area (cm 2 ) (i.e., AABD) or volume (cm 3 ) (i.e.
  • the relative amount of FGT may be an estimate of the surface area of FGT relative to non-FGT (as a percentage (i.e. ABD %)) or an estimate of the volume of the FGT to the volume of the breast (i.e., VBD %).
  • Another way may be to determine absolute volumetric breast density (i.e., AVBD) which may be the measured volume of fibro-glandular tissue in a subject's breast in cubic centimeters.
  • Mammographic breast density may be determined by various methods, including but not limited to, mammography, digital mammography, magnetic resonance imaging (MRI), ultrasound, digital breast tomosynthesis (DBT), virtual touch tissue imaging quantification (VTIQ), and combinations thereof.
  • MBD may be qualitatively assessed, via 2-D determinations and/or using the BI-RADS® density categories, with 1 (or a) being least dense and 4 (or d) being the densest. MBD may also be qualitatively and/or quantitatively assessed via 3-D determinations and/or using volumetric measurements of the breast, such as determining the volumetric breast density, which is the proportion of fibro-glandular (dense) tissue relative to the total volume of tissue in the breast (e.g., fibro-glandular (dense) tissue and fat in the breast). Another way is to determine absolute volumetric breast density (AVBD), which is the measured volume of fibro-glandular tissue in a subject's breast in cubic centimeters.
  • AVBD absolute volumetric breast density
  • MBD fibro-glandular tissue
  • assessments of MBD via 3-D determinations may also account for the heterogeneity of dense tissue within the breast.
  • Several tests that may be used to measure MBD including but not limited to, VOLPARA, QUANTRA, CUMULUS, and methods taking into account the volume of fibro-glandular tissue (cm 3 ).
  • patient or “subject” means an animal, including the human species that is treatable with the compositions, methods, and kits of the present disclosure.
  • patient or “patients” is intended to refer to both the male and female gender unless one gender is specifically indicated or clear from the context.
  • patient may also refer to a female to male transgender.
  • peri-menopause or “menopausal transition” means the period of time around menopause during which a woman's body makes its natural transition toward permanent infertility (menopause). Women may start peri-menopause at different ages, and may notice signs of progression toward menopause, such as menstrual irregularity, during their 40's, or even as early as their mid-30's. During peri-menopause, estrogen levels may rise and fall unevenly, menstrual cycles may lengthen or shorten, and menstrual cycles may begin in which the ovaries do not release an egg (ovulate). During peri-menopause, other menopause-like symptoms may be experienced, including, but not limited to, hot flashes, sleep problems, and/or vaginal dryness.
  • peri-menopausal symptoms is understood to include but is not limited to, menstrual irregularity; hot flashes and sleep problems; mood changes; mood swings; irritability; depression; vaginal dryness; urinary or vaginal infections; urinary incontinence; decreasing fertility; changes in sexual arousal or desire; bone loss; fragile bones; osteoporosis; or changing cholesterol levels, such as an increase in low-density lipoprotein (LDL) cholesterol, or a decrease in high-density lipoprotein (HDL) cholesterol and combinations thereof.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • pharmaceutically acceptable means those compounds, agents, materials, compositions, excipients, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and/or animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit and/or risk ratio.
  • pellet means a solid formulation implant comprising an effective amount of an androgen and an effective amount of an aromatase inhibitor.
  • the pellet or implant may have different suitable shapes and sizes, for example, spherical, cylindrical, rectangular, square or combinations thereof. It may have angular edges or round edges. In certain embodiments, the pellet or implant may be compressed.
  • the term “pharmaceutical formulation” means a formulation comprising an effective amount of an androgen and an effective amount of an aromatase inhibitor when the formulation is administered to a warm-blood subject the formulation provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor. There may be at least 2, 3 or 4 different time periods. These time periods vary depending on one or more of the following: formulation, delivery system, drug concentrations, and individual physiological variabilities during the time to complete, or substantially complete, formulation absorption. Typically, the formulation's absorption is not less than 3 months and not more than 5 months.
  • the formulation may be delivered via a transdermal patch.
  • the formulation may be delivered via a solid form such as a subcutaneous pellet.
  • the formulation may be delivered via a solid form such as a compressed subcutaneous pellet.
  • post-menopausal woman is understood to include not only a woman of advanced age who has passed through menopause but also a woman who has had her ovaries removed or destroyed by other means or for some other reason has suppressed estrogen production, such as one who has undergone long-term administration of corticosteroids, suffer from Cushing's syndrome or has gonadal dysgenesis.
  • subject is an animal including the human species that is treatable with the compositions, methods, and kits of the present disclosure.
  • the term “subject” or “subjects” is intended to refer to both the male and female gender unless one gender is specifically indicated or clear from the context.
  • the term “subject” may also refer to a female to male transgender.
  • treatment includes preventative (e.g., prophylactic) treatment and/or palliative treatment and “treating” as used herein refers to the act of providing preventative and/or palliative treatment.
  • volumetric breast density percentage means the proportion or percentage of fibro-glandular (dense) tissue in volume relative to the total volume of tissue in the breast. For example, this may be measured using the Volpara SolutionTM software algorithms. In the Volpara SolutionTM software algorithms, VBD % is referred to as volumetric breast density percentage. There are several other tests that may be used to measure VBD %, including but not limited to, QUANTRA, CUMULUS, and methods taking into account the volume of fibro-glandular tissue.
  • FIG. 1 shows the data of the serum concentration for the androgen and plasma concentration for the aromatase inhibitor over 84 days, according to certain exemplary embodiments.
  • FIG. 2 shows the data of FIG. 1 but expanded to further illustrate the first 42 days.
  • FIG. 3 shows the serum concentration of testosterone in 11 subjects up to 7 days post dose, according to certain exemplary embodiments.
  • FIG. 4 shows the serum concentration of testosterone in 11 subjects up to 85 days post dose, according to certain exemplary embodiments.
  • FIG. 5 shows the plasma concentration of anastrozole in 11 subjects over 336 hours post dose, according to certain exemplary embodiments.
  • FIG. 6 shows the plasma concentration of anastrozole in 11 subjects over 1680 hours post dose, according to certain exemplary embodiments.
  • FIGS. 7 A-B illustrate the anastrozole absorption rates, according to certain embodiments.
  • FIGS. 8 A-B illustrate the plasma anastrozole concentration post implantation, according to certain embodiments.
  • FIG. 9 shows the frequency of observation post implantation in Example 3.
  • FIG. 10 illustrates an example of a flow chart of models tested in Example 3.
  • FIG. 11 shows the final structure model used in Example 3.
  • FIGS. 12 A-B shows the population and individual predictions used in Example 3.
  • FIGS. 13 A-C illustrate 11 individual plots of observed and predicted plasma concentrations of anastrozole, according to certain embodiments.
  • FIG. 14 shows a visual predictive check (VPC) of anastrozole concentration post implantation used in Example 3.
  • FIGS. 15 A-B shows one versus two compartment model used in Example 3.
  • FIG. 16 displays predictions for patient 10 from several different input models used in Example 3.
  • FIG. 17 diagrammatically illustrates the effect of the androgenic agent testosterone and the aromatase inhibitor (T+Ai) on breast tissue immunoreactivity.
  • FIG. 18 shows the results of western blot analysis of CD36 protein in three explant samples of normal breast tissue obtained from three peri-menopausal women at baseline and after 24 hours cultivation.
  • FIG. 19 A are mammographic images before (left) and after (right) treatment in accordance with the present disclosure showing a substantial reduction in breast size and density.
  • FIG. 19 B are Volpara SolutionTM breast volume and density measurements (left) and after (right) treatment for the patient of FIG. 19 A showing a breast volume reduction (58%) back to pre-morbid size and fibro-glandular tissue reduction (71%).
  • FIG. 19 C are magnetic resonance images (MRI) of the breast of the patient of FIG. 19 before treatment (left) and after treatment for three subsequent years showing a reversal of the extreme background parenchymal enhancement on MRI for the subsequent 3 year period following treatment cessation.
  • MRI magnetic resonance images
  • FIG. 20 A are mammographic images for another patient before (left) and after (right) treatment in accordance with the present disclosure showing a substantial reduction in breast size and density.
  • FIG. 20 B are Volpara SolutionTM breast volume and density measurements before (left) and after (right) treatment for the patient of FIG. 20 A showing a breast volume reduction (10%) back to pre-morbid size and a reduction in fibro-glandular volume (41%).
  • FIG. 21 A shows mammographic images for another patient before (left) and after (right) treatment in accordance with the present disclosure showing a substantial reduction in breast size and density.
  • FIG. 21 B are Volpara SolutionTM breast volume and density measurements before (left) and after (right) treatment for the patient of FIG. 21 A showing a breast volume reduction (32%) back to pre-morbid size and a reduction in fibro-glandular volume (52%).
  • FIG. 22 A are magnetic resonance images (MRI) of the breast of further patient before treatment (left) and after treatment (right) in accordance with the present disclosure showing a complete reversal of MRI extreme background parenchymal enhancement.
  • FIG. 22 B are mammographic images before (left) and after (right) of the breast of the patient of FIG. 22 B showing a reduction in breast size and density.
  • FIG. 22 C are Volpara SolutionTM breast volume and density measurements before (left) and after (right) treatment for the patient of FIG. 22 B showing a breast volume reduction (23%) back to pre-morbid size and a reduction in fibro-glandular volume (36%).
  • FIG. 23 A shows extreme breast swelling in another patient demonstrated by mammography before treatment treatment in accordance with the present disclosure.
  • FIG. 23 B shows a magnetic resonance image (MRI) of intense breast metabolic activity with little fat demonstrated as shown by extreme background parenchymal enhancement in the breast of the patient of FIG. 23 A .
  • MRI magnetic resonance image
  • FIG. 24 A shows a magnetic resonance image (MRI) of another patient with granuloma formation in the retroareolar space with an enlarged reactive axillary lymphnode.
  • MRI magnetic resonance image
  • FIG. 24 B is an MRI image of the breast of the patient of FIG. 24 A showing resolution of the granulomata and reduction in size of the axillary lymph node after treatment in accordance with the present disclosure.
  • the present disclosure is directed, at least in part, to providing drug delivery systems with a multi-phasic sustained release pattern comprising an androgenic agent and an aromatase inhibitor in a compressed pellet that unexpectedly overcomes the problem of obtaining high intra-tissue DHT to oestradiol ratio when subcutaneously delivered to a subject.
  • the desired effect is to have an early peak of serum testosterone which is rapidly blocked by a high level of aromatase inhibitor allowing the induction of 5 alpha reductase conversion of testosterone to DHT.
  • These disease conditions include but not exclusively, high mammographic breast density, breast pain, endometriosis, male gynaecomastia, perimenopausal and premenstrual tissue aberrations, autoimmune inflammatory mastitis (which includes conditions such as idiopathic inflammatory macromastia, plasma cell mastitis, and granulomatous mastitis).
  • phase I shows a rapid increase in both serum testosterone and plasma anastrozole in the subjects. This increase results in a rapid tissue induction of five alpha reductase and the profound inhibition of aromatase.
  • the high tissue level of testosterone is rapidly converted to DHT with conversion to oestradiol being completely blocked, or substantially blocked.
  • this first phase lasts for approximately 8 days as illustrated by the vertical bar separating phase 1 from phase 2.
  • the time period for phase 1 may vary depending on a number of factors, including, but not limited to, the biology of a particular subject, the formulation of the pellet and/or the manufacturing parameters used for making the pellet.
  • phase II time period lasts for approximately 14 days.
  • phase 2 it is desirable to recondition the enzymatic system to cause a sustained high intra-tissue level of anastrozole that continues to allow the induction of 5 alpha reductase to work unopposed, or substantially unopposed, to aromatase conversion of testosterone and oestradiol.
  • This reconditioning leads to a fall in serum testosterone avoiding excessive androgenic side-effects and persistent adduction of five alpha reductase.
  • this second phase lasts for approximately 14 days as illustrated by the vertical bar separating phase 2 from phase 3.
  • the time period for phase 2 may vary depending on a number of factors, including, but not limited to, the biology of a particular subject, the formulation of the pellet and/or the manufacturing parameters used for making the pellet.
  • phase III the anastrozole level falls rapidly allowing some conversion of testosterone to oestradiol and avoiding significant usage and depletion symptoms which may result from sustained high levels of anastrozole which would be observed, for example, in a zero-order release pattern.
  • the induced 5 alpha reductase continues to convert the elevated testosterone to DHT within the target tissue until the implant runs out of the substrate and is replaced.
  • this third phase lasts at least until the pellet is depleted.
  • the subjects were tracks for another 70 days.
  • the time period for phase 3 may vary depending on a number of factors, including, but not limited to, the biology of a particular subject, the formulation of the pellet and/or the manufacturing parameters used for making the pellet.
  • Certain embodiments may be used for treating extreme mammographic breast density. Serum reproductive hormone levels poorly correlate with intra-tissue levels due to significant metabolism to either inactive or active metabolites of prohormones such as testosterone. In certain disease states such as extreme mammographic breast density, there is overexpression of enzymes known to convert testosterone to either estrogen or dihydrotestosterone-10 times more potent as an androgen than testosterone. By altering the androgen to estrogen ratio in high mammographic breast density that there is the potential for reduction of that density and therefore reduce the incidence of breast cancer. The reduction in density is also applicable to situations such as gynecomastia in men where there is an excessive estrogen to androgen within the tissue.
  • a subcutaneous pellet has been designed to facilitate a multi-phasic sustained release pattern.
  • anastrozole and testosterone are combined in a specific fashion and compression into a pellet that has undergone specific compression the resultant pharmacokinetics of facilitates this multi-phasic sustained release of both active ingredients.
  • anastrozole facilitates the conversion of testosterone through five alpha reduction to dihydrotestosterone and facilitates an androgenic excess over estrogenic environment.
  • a significantly low level is maintained so as to not cause alterations in either hypothalamic-pituitary function or induction of total body aromatase inhibition as is seen in higher concentrations of aromatase inhibitors such as when they are taken orally.
  • This then allows slow of testosterone into the tissues in which there has been an induction of the five-alpha reductase in the somatic system to continue the perturbation of the antigenic environment.
  • This unique multi-phasic sustained release pattern is useful to establish alteration in tissue hormone levels without causing significant physiological alterations in other serum reproductive hormone levels and the resultant potential for adverse side-effects.
  • Certain embodiments may be used for treating one or more of the following: high breast density and breast stiffness.
  • High breast density and/or breast stiffness is not normal, rather it is pathological; and it is something which may be addressed by effective amounts of an androgenic agent and/or an effective amount of an aromatase inhibitor rather than being treated as a lifestyle modification (e.g., diet and exercise) which has not proven to be successful in pre-menopausal, peri-menopausal and/or post-menopausal women.
  • a lifestyle modification e.g., diet and exercise
  • Certain embodiments are directed to pharmaceutical formulations that may be used in methods for providing an individualized reduction of one or more of the following: mammographic breast density and breast stiffness in a patient in need thereof, comprising (i) determining the patient's MBD and/or breast stiffness; (ii) optionally, measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month; (iii) determining adjusted doses of an androgenic agent and aromatase inhibitor taking into account the patient's body weight, total body fat, MBD, age, and free androgenic index; and (iv) administering the adjusted dose to said patient.
  • the measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month may include taking a blood sample and measuring the amount of free androgenic agent (or testosterone) in the patient's serum.
  • Certain embodiments are directed to pharmaceutical formulations may be used in methods for providing an individualized reduction of one or more of the following: VBD %, AVBD and breast stiffness in a patient in need thereof, comprising (i) determining the patient's VBD % and/or AVBD and/or breast stiffness; (ii) optionally, measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month; (iii) determining adjusted doses of an androgenic agent and/or aromatase inhibitor taking into account the patient's body weight, total body fat, VBD % and/or AVBD, age, and free androgenic index; and (iv) administering the adjusted dose to said patient.
  • the measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month may include taking a blood sample and measuring the amount of free androgenic agent (or testosterone) in the patient's serum.
  • Certain embodiments are directed to pharmaceutical formulations may be used in methods for providing an individualized reduction of one or more of the following: ABD %, AABD, and breast stiffness in a patient in need thereof, comprising (i) determining the patient's VBD % and/or AVBD and/or breast stiffness; (ii) optionally, measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month; (iii) determining adjusted doses of an androgenic agent and/or aromatase inhibitor taking into account the patient's body weight, total body fat, ABD % and/or AABD, age, and free androgenic index; and (iv) administering the adjusted dose to said patient.
  • the measuring the patient's free androgenic index and/or alterations in the patient's free androgenic index over a period of time of at least one month may include taking a blood sample and measuring the amount of free androgenic agent (or testosterone) in the patient's serum.
  • Certain embodiments are directed to pharmaceutical formulations may be used for reducing one or more of the following: mammographic breast density and breast stiffness in a patient in need thereof, wherein the pharmaceutical formulation increases sensitivity of breast imaging detections by mammography, digital mammography, magnetic resonance imaging (MRI), ultrasound, digital breast tomosynthesis (DBT), virtual touch tissue imaging quantification (VTIQ), or combinations thereof.
  • mammographic breast density and breast stiffness in a patient in need thereof
  • the pharmaceutical formulation increases sensitivity of breast imaging detections by mammography, digital mammography, magnetic resonance imaging (MRI), ultrasound, digital breast tomosynthesis (DBT), virtual touch tissue imaging quantification (VTIQ), or combinations thereof.
  • MRI magnetic resonance imaging
  • DBT digital breast tomosynthesis
  • VTIQ virtual touch tissue imaging quantification
  • Certain embodiments are directed to pharmaceutical formulations may be used for reducing one or more of the following: mammographic breast density and breast stiffness in a patient in need thereof, wherein the pharmaceutical formulation increases detection of breast cancer developing in the patient.
  • Certain embodiments are directed to pharmaceutical formulations may be used for reducing one or more of the following: VBD %, AVBD, and breast stiffness in a patient in need thereof, wherein the pharmaceutical formulation increases detection of breast cancer developing in the patient.
  • Certain embodiments are directed to pharmaceutical formulations may be used for reducing one or more of the following: ABD %, AABD, and breast stiffness in a patient in need thereof, wherein the pharmaceutical formulation increases detection of breast cancer developing in the patient.
  • compositions as disclosed herein may be used to affect one or more of the following in a patient: reducing mammographic breast density; treating mammographic breast density; reducing breast stiffness; treating breast stiffness; reducing mammographic breast density in a patient having a breast with a mammographic breast density of 7.5% or greater, reducing mammographic breast density in a patient having a breast with a BI-RADS® score of 3 or 4 (or c or d); inducing breast involution in a patient; inducing net cell death over proliferation in a breast of a patient; inducing net extracellular matrix degradation over development of extracellular matrix in a breast of a patient; methods of reversing cell number and mammographic breast density in a breast of a peri-menopausal patient; reducing mammographic breast density and peri-menopausal symptoms in a patient, and prophylaxis or treatment of autoimmune inflammatory mastitis (e.g., idiopathic inflammatory macromastia,
  • compositions and combination treatments of an androgenic agent and an aromatase inhibitor (Ai) as described herein may be useful in pre-menopausal, peri-menopausal woman, and/or post-menopausal woman.
  • peri-menopause woman For example, high breast density in peri-menopause woman is known as a risk for developing breast cancer.
  • the dense tissue in peri-menopausal women is not considered normal and has pathological implications. This increase in breast density may be due to lifelong exposure to high levels of estrogen and progesterone in the presence of a low testosterone environment.
  • the present inventors have discovered, among other things, that pre-menopausal, peri-menopausal and/or post-menopausal woman who receive via a multi-phasic pattern formulation an effective amount of an androgenic agent such as testosterone and an effective amount of an aromatase inhibitor (such as anastrozole) may show a reduction in breast density and/or breast stiffness.
  • an androgenic agent such as testosterone
  • an aromatase inhibitor such as anastrozole
  • the present inventors have also discovered that pre-menopausal, peri-menopausal and/or post-menopausal woman who receive via a multi-phasic pattern formulation an effective amount of testosterone and an effective amount of an aromatase inhibitor (such as anastrozole) may show induction of breast involution and/or net cell death over proliferation.
  • an effective amount of an aromatase inhibitor delivered to a subject via a multi-phasic pattern formulation to the subject's breast tissue may be used to stop the conversion of testosterone to estrogen and thus allow testosterone to invoke an involution of the breast cells.
  • Certain further embodiments are directed to the prophylaxis or treatment of autoimmune inflammatory mastitis (AIM), which includes the conditions of idiopathic inflammatory macromastia, plasma cell mastitis and granulomatous mastitis as described above.
  • AIM autoimmune inflammatory mastitis
  • Breast tissue may be a target tissue in autoimmune diseases, this process being favoured by the hormonal milieu (Touraine, 2005).
  • Autoimmune breast tissue compared to normal breast tissue, has been demonstrated to have elevated aromatase (that converts androgens to estradiol) and other factors associated with inflammation, such as IGF2, EGFR, TGF- ⁇ , PDGFR- ⁇ and ⁇ (Das, 2019).
  • the breast is unique in that it requires an immunoprivilaged environment for lactation and a rapid remodelling of tissue following lactation (called lactational involution) that requires immunosuppression to avoid autoimmunity (Dawson, 2020).
  • lactational involution Central to this is the formation of regulatory T (Treg) cells that are able to inhibit proliferation and cytokine production in effector T cells and play a major role in immune responses and prevention of autoimmune disease.
  • Treg regulatory T
  • T cell receptor (TCR) gene segments are rearranged to generate a diverse TCR repertoire necessary for immunity to invading pathogens. An unintended consequence of this diversity is the recognition of self-antigen, which can result in autoimmunity.
  • T cells Two fundamental processes promote tolerance to self in the thymus (referred to as central tolerance) prior to their release into the periphery: (1) negative selection, whereby autoreactive T cells are eliminated; and (2) generation of CD4 + forkhead box P3 (Foxp3) + regulatory T (Treg) cells.
  • CD36 facilitates transfer of cell-surface antigens to promote tolerance to host antigens during homeostasis.
  • a master regulator of Treg cell development and function is transcription factor Foxp3.
  • Testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro (Walecki, 2015). High levels of Treg cells in breast tumours have reduced the capacity of immunotherapies due to Treg cell immunosuppressive capacity. Targeting Treg cells has resulted in unacceptable autoimmunity side-effects that limits the use of this pathway.
  • the impact of testosterone and an aromatase inhibitor on breast tissue immunoreactivity is diagrammatically illustrated in FIG. 17
  • CD36 is found on platelets, erythrocytes, monocytes, differentiated adipocytes, skeletal muscle, mammary epithelial cells, spleen cells and some skin microdermal endothelial cells.
  • CD36 is downregulated by estradiol control in hormonally sensitive breast cancer cell lines (Uray, 2004); b) overexpression of CD36 in fibroblasts inhibits the formation of solid tumors in subtypes of breast cancer models (Cheng, 2020); and c) CD36 is profoundly suppressed in non-malignant tissue of women at higher risk of developing breast cancer due to high mammographic density (HMD) (i.e., low fat containing breast tissue) (DeFilippis, 2014).
  • HMD mammographic density
  • Tlsty's group (DeFilipis, 2014) has suggest the following cascade: i) elevated basal DNA damage in HMD epithelial cells results in increased activin A secretion; ii) activin A binds to its receptor on adjacent fibroblasts and activates the MAPK pathway; iii) MAPK pathway activation results in PPAR ⁇ phosphorylation and inhibition; iv) PPAR ⁇ inhibition leads to decreased CD36 transcription and subsequently, the induction of the desmoplastic-like phenotypes observed in HMD tissues.
  • induction of CD36 expression in breast tissue may be obtained by treating the tissue with an effective amount of an androgenic agent in combination with an effective amount of an aromatase inhibitor, and the present disclosure expressly extends to such methods and use in a patient e.g., a peri-menopausal, menopausal or post-menopausal woman.
  • a subcutaneous pellet is described herein for facilitating a multi-phasic sustained release pattern for alteration in androgen to estrogen ratio in the prophylaxis or treatment of autoimmune diseases or conditions.
  • Anastrozole and testosterone can be combined and compressed into a pellet as described herein to provide pharmacokinetics facilitating this multi-phasic sustained release of both active ingredients. This release pattern ensures that early high levels of testosterone are associated with very high levels of aromatase inhibitor, so only DHT is presented to the inflamed breast tissue and that the testosterone is not converted to estradiol (which is pro-inflammatory).
  • the induction of 5 alpha reductase from the first phase continues to ensure maintenance of high levels of DHT to exert an anti-inflammatory effect, whilst there is a more rapid decline in anastrozole.
  • the third delivery phase then allows slow release of testosterone into the tissues in which there has been an induction of the five-alpha reductase in the somatic system to continue the perturbation of the antigenic environment.
  • This unique multi-phasic sustained release pattern may establish alteration in tissue hormone levels substantially without causing significant physiological alterations in other serum reproductive hormone levels and the resultant potential for adverse side-effects.
  • the impact of the androgen testosterone and the aromatase inhibitor is anastrozole as described herein on breast tissue immunoreactivity is illustrated in FIG. 17 .
  • compositions, delivery systems and/or methods of use is the rapid early induction of conversion of testosterone to dihydrotestosterone in the tissue where an early response may reset the homeostatic mechanism in a beneficial way and reduce the estradiol to androgen ratio in the tissue. This may result in one or more of the following advantages:
  • a diagnosing or treating physician may use one or more exams/tests to evaluate, characterize, and/or diagnose, a breast density, including but not limited to, mammography, digital mammography, magnetic resonance imagery (MRI), ultrasound, digital breast tomosynthesis (DBT), virtual touch tissue imaging quantification (VTIQ), or combinations thereof.
  • mammography digital mammography
  • MRI magnetic resonance imagery
  • DBT digital breast tomosynthesis
  • VTIQ virtual touch tissue imaging quantification
  • the physician may also use other indicia, such as medical history or family history (to account for a genetic predisposition to breast density), and/or qualitative assessments of MBD, such as BI-RADS® (e.g., 5 th edition, using Breast Composition categories of “a” (the breasts are almost entirely fatty), “b” (there are scattered areas of fibro-glandular density), “c” (the breasts are heterogeneously dense, which may obscure small masses), and “d” (the breasts are extremely dense, which lowers the sensitivity of mammography) (D'Orsi C J, Sickles E A, Mendelson E B, Morris E A et al. (2013). ACR BI - RADS® Atlas, Breast Imaging Reporting and Data System . Reston, Va.: American College of Radiology).
  • BI-RADS® e.g., 5 th edition, using Breast Composition categories of “a” (the breasts are almost entirely fatty), “b” (there are scattered areas of fibro-
  • Breast pain is a significant problem in female health. Breast pain is also associated with increases in VBD % and/or AVBD, breast stiffness, the risk of breast cancer or combinations thereof. Certain embodiments are directed to the use of an androgen agent and an aromatase inhibitor to reduce the breast pain in a patient.
  • Certain embodiments are directed to the use of a subcutaneous pellet comprising: an effective amount of anastrozole and an effective amount of testosterone.
  • a subject is provided between 0.5-10 mg anastrozole (2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile)) and between 60-120 mg testosterone in a pharmaceutical formulation that has been compressed into a pellet.
  • a subject is provided between 4-6 mg anastrozole and between 60-120 mg testosterone in a pharmaceutical formulation that has been compressed into a pellet.
  • a subject is provided approximately 4 mg anastrozole and approximately 80 mg testosterone in a pharmaceutical formulation that has been compressed into a pellet.
  • Other androgenic agents may also be used.
  • the duration of treatment for administration of the subcutaneous pellet comprising: anastrozole and testosterone may vary between 2 weeks to 4 weeks, 3 months to 3 years, 6 months to 2 years, 3 months to 5 years, 1 year to 5 years, or 1 year to 3 years.
  • the duration of treatment may be approximately 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years.
  • the duration of treatment may be at least 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 year or 4 years.
  • the duration of treatment may be approximately 3 years.
  • the treatment may be applied to one or more of the following; a reduction in ABD %, a reduction in AABD, a reduction in VBD %; a reduction in AVBD; a reduction in breast pain; a reduction in breast stiffness; a reduction in breast elasticity; a reduction in macromastia; a reduction in breast cysts; an improvement in mammographic diagnostic sensitivity and a reduction in false positives; an increase in the ratio between fibro-glandular and adipose tissue; and a stabilization and/or an increase in levels of androgen receptor expression.
  • Certain embodiments are directed to the use of a subcutaneous pellet comprising: an effective amount of letrozole and an effective amount of testosterone.
  • a patient is provided a subcutaneous pellet comprising an 0.5-20 mg letrozole (4,4′-((1H-1,2,4-triazol-1 yl)methylene)dibenzonitrile) and between 40-130 mg testosterone for subcutaneous administration.
  • a patient is provided a subcutaneous pellet comprising approximately 10 mg letrozole (4,4′-((1H-1,2,4-triazol-1 yl)methylene)dibenzonitrile) and between 40-130 testosterone for subcutaneously administration.
  • Other androgenic agents may also be used.
  • the duration of treatment for administration of the subcutaneous pellet comprising letrozole and testosterone may vary between 2 weeks to 4 weeks, 3 months to 3 years, 6 months to 2 years, 3 months to 5 years, 1 year and 5 years or 1 year to 3 years. In certain embodiments, the duration of treatment may be approximately 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years, or 3 years. In certain embodiments, the duration of treatment may be at least 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 year or 4 years. In certain embodiments, the duration of treatment may be approximately 3 years.
  • the treatment may be applied to one or more of the following: a reduction in ABD %, a reduction in AABD, a reduction in VBD %; a reduction in AVBD; a reduction in breast pain; a reduction in breast stiffness; a reduction in breast elasticity; a reduction in macromastia; a reduction in breast cysts; an improvement in mammographic diagnostic sensitivity and a reduction in false positives; an increase in the ratio between fibro-glandular and adipose tissue; and a stabilization and/or an increase in levels of androgen receptor expression.
  • Certain embodiments are directed to the use of a subcutaneous pellet comprising: an effective amount of exemestane and an effective amount of testosterone.
  • a patient is provided a subcutaneous pellet comprising exemestane 10-75 mg 6-Methylideneandrosta-1,4-diene-3,17-dione and between 40-130 mg testosterone for subcutaneously administration.
  • Other androgenic agents may also be used.
  • the duration of treatment for administration of the exemestane and the testosterone may vary between 2 weeks to 4 weeks, 3 months to 3 years, 6 months to 2 years, 3 months to 5 years, 1 year and 5 years, or 1 year to 3 years.
  • the duration of treatment may be approximately 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years. In certain embodiments, the duration of treatment may be at least 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 year or 4 years. In certain embodiments, the duration of treatment may be approximately 3 years.
  • the treatment may be applied to one or more of the following: a reduction in ABD %, a reduction in AABD, a reduction in VBD %; a reduction in AVBD; a reduction in breast pain; a reduction in breast stiffness; a reduction in breast elasticity; a reduction in macromastia; a reduction in breast cysts; an improvement in mammographic diagnostic sensitivity and a reduction in false positives; an increase in the ratio between fibro-glandular and adipose tissue; and a stabilization and/or an increase in levels of androgen receptor expression.
  • esters as noted herein, involves functionalization of hydroxyl and/or carboxyl groups that may be present, as will be appreciated by those skilled in the arts of pharmaceutical chemistry and drug delivery.
  • the 17-hydroxyl group of the testosterone molecule is generally caused to react with a suitable organic acid under esterifying conditions, such conditions typically involving the use of a strong acid such as sulfuric acid, hydrochloric acid, or the like, and a temperature sufficient to allow the reaction to proceed at reflux.
  • Esters may be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
  • an effective amount of an androgenic agent may vary among androgenic agents.
  • the effective amount per day of testosterone may also vary.
  • an effective amount of testosterone may be delivered in the form of a subcutaneous implant.
  • an effective amount of testosterone may be between 40 and 200 mg.
  • the effective amount of testosterone may be between 40 to 120 mg, for example, 20 mg, 40 mg, 60 mg 80 mg, 100 mg or 120 mg.
  • an effective amount of testosterone may be delivered in the form of a subcutaneous implant, such as a subcutaneous pellet, containing between 40 to 200 mg testosterone, such as between 40 to 150 mg, 40 to 100 mg, 100 to 200 mg, 50 to 150 mg, 50 to 100 mg, 40 to 100 mg, 30 to 80 mg, 40 to 90 mg, 40 to 90 mg, 40 to 80 mg, 40 to 70 mg, 40 to 60 mg, 40 to 50 mg, 40 to 100 mg, 60 to 100 mg, 45 to 75 mg or 40 to 45 mg testosterone.
  • a subcutaneous implant such as a subcutaneous pellet, containing between 40 to 200 mg testosterone, such as between 40 to 150 mg, 40 to 100 mg, 100 to 200 mg, 50 to 150 mg, 50 to 100 mg, 40 to 100 mg, 30 to 80 mg, 40 to 90 mg, 40 to 90 mg, 40 to 80 mg, 40 to 70 mg, 40 to 60 mg, 40 to 50 mg, 40 to 100 mg, 60 to 100 mg, 45 to 75 mg or 40 to 45 mg testosterone.
  • an effective amount per day of methyltestosterone may vary.
  • the effective amount of methyltestosterone may be between 0.1 mg to 10 mg, such as between 0.5 mg to 9 mg, 2 mg to 8 mg, 3 mg to 7 mg, or 4 mg to 5 mg.
  • the effective amount of methyltestosterone may be 0.5 mg, 1.25 mg or 2.5 mg.
  • the effective amount of androgenic agent used in conjunction with an aromatase inhibitor may be relatively lower than a standard dose because of low levels of sex hormone binding globulin in the patient's serum which may be caused by the aromatase inhibitor.
  • Sex hormone binding globulin binds an androgenic agent (e.g., testosterone) and transports it around the body. Its production is regulated by several mechanisms, but one of the effectors of its level is the amount of estrogen in the serum: the higher the estrogen, the higher the sex hormone binding globulin and the lower the free androgenic agent. Conversely, the lower the estrogen, the lower the sex hormone binding globulin, and the higher the free androgenic agent, which means the androgenic agent has higher bioavailability. Thus, after menopause, as the estrogen level falls, the sex hormone binding globulin level falls and the free androgenic agent such as testosterone rises. This free androgenic agent has multiple functions, as the androgen receptor is expressed in all cells of the body.
  • an androgenic agent e.g., testosterone
  • the dosage levels below the lower limit of the aforesaid range of the androgenic agent may be more than adequate, while in other cases still larger doses above the upper limit of the aforesaid range may be employed without causing any harmful side effects.
  • the aromatase inhibitor may be, for example, a steroidal aromatase inhibitor, a nonsteroidal aromatase inhibitor, and/or isomers thereof.
  • Steroidal aromatase inhibitors developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid.
  • steroidal aromatase inhibitors include but are not limited to, exemestane (Aromasin®) and formestane. Additional examples include mechanism-based steroidal aromatase inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase.
  • the aromatase inhibitor is exemestane.
  • Nonsteroidal aromatase inhibitors may be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Examples of non-steroidal aromatase inhibitors include anastrozole, exemestane, or letrozole. In certain embodiments, the aromatase inhibitor is either anastrozole or letrozole. In certain embodiments, the aromatase inhibitor is anastrozole.
  • Aromatase inhibitors often include third-generation aromatase inhibitors, such as anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®). These third-generation aromatase inhibitors have brought a change in the therapeutic approach to patients with hormone-sensitive breast cancer. Such aromatase inhibitors are specific in their action in that they virtually ablate estrogen in the serum and thus lower sex hormone binding globulin, which enables the achievement of a synergistic effect.
  • third-generation aromatase inhibitors such as anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®).
  • the aromatase inhibitor may be selected from the group consisting of anastrozole, exemestane, or letrozole. In certain embodiments, the aromatase inhibitor is either anastrozole or letrozole. In certain embodiments, the aromatase inhibitor is anastrozole.
  • a method for determining if the patient has a breast with a BI-RADS® score of 3 or 4 (or c or d); a breast with a mammographic breast density of 7.5% or greater, a mammographically dense breast; a breast with the same or more breast tissue than fat; a breast with more breast tissue than fat; breast cancer or combinations thereof.
  • the patient has or is diagnosed with having, a breast with a BI-RADS® score (1-4 scale) in the range of between 2 and 4, for example, between 2 and 3, or between 3 and 4. In certain embodiments, the patient has or is diagnosed with having, a breast with a BI-RADS® score of 2 or more, for example, a BI-RADS® score of 3 or 4, or a BI-RADS® score of 4.
  • the patient has or is diagnosed with having, a breast with a BI-RADS® score (a-d scale) in the range of between b and d, for example, between b and c, or between c and d.
  • the patient has or is diagnosed with having, a breast with a BI-RADS® score of b or more, for example, a BI-RADS® score of c or d, or a BI-RADS® score of d.
  • the patient has or is diagnosed with having, a breast with a mammographic breast density of 7.5% or greater, for example, a mammographic breast density of 10% or greater, 15% or greater, 20% or greater, 30% or greater, 50% or greater, 70% or greater, or 95% or greater.
  • the patient has or is diagnosed with having, a breast with a VBD % of 7.5% or greater, for example, a VBD % of 10% or greater, 15% or greater, 20% or greater, 30% or greater, 50% or greater, 70% or greater, or 95% or greater.
  • the patient has or is diagnosed with having, a breast with an ABD % of 7.5% or greater, for example, an ABD % of 10% or greater, 15% or greater, 20% or greater, 30% or greater, 50% or greater, 70% or greater, or 95% or greater.
  • the patient has or is diagnosed with having, a breast with a BI-RADS® score of 3 (or c) and a mammographic breast density of 7.5% or greater, for example, a mammographic breast density of 10% or greater, 15% or greater, 20% or greater, 30% or greater, 50% or greater, 70% or greater, or 95% or greater.
  • the patient has or is diagnosed with having, a breast with a BI-RADS® score of 4 (or d) and a mammographic breast density of 7.5% or greater, for example, a mammographic breast density of 10% or greater, 15% or greater, 20% or greater, 30% or greater, 50% or greater, or greater, or 95% or greater.
  • the patient has or is diagnosed with having, a breast with a VBD % in the range of between 1% to 100%, for example, a VBD % of between 1% and 24%, 5% to 100%, 5% to 95%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 25%, 5% to 20%, 10% to 100%, 10% to 95%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 25%, 10% to 20%, 25% to 100%, 25% to 75%, 25% to 50%, 25% to 49%, 30% to 100%, 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 95%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 95%, 50% to 90%, 40% to 80%, 40% to 70%, 40%
  • the patient has or is diagnosed with having, a breast with a ABD % in the range of between 1% to 100%, for example, a ABD % of between 1% and 24%, 5% to 100%, 5% to 95%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 25%, 5% to 20%, 10% to 100%, 10% to 95%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 25%, 10% to 20%, 25% to 100%, 25% to 75%, 25% to 50%, 25% to 49%, 30% to 100%, 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 95%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 95%, 50% to 90%, 40% to 80%, 40% to 70%, 40%
  • the patient has, or is diagnosed with having, a breast with a ABD % in the range of between 50% to 100%. In certain embodiments, the patient has or is diagnosed with having, a mammographically dense breast, for example, a breast having about the same or more breast tissue than fat.
  • the patient is a peri-menopausal woman or a post-menopausal woman. In certain embodiments, the patient is a perimenopausal woman.
  • the pharmaceutical formulation may be used to reduce or decrease the patient's BI-RADS® score one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the patient's BI-RADS® score by 1 or more points one or more annual intervening mammographic detections, such as, by 2 or more, 3 or 4, or 4 points one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the patient's BI-RADS® score by 1 point one or more annual intervening mammographic detections, for example, by 2, 3, or 4 points one or more annual intervening mammographic detections.
  • the pharmaceutical formulation maintains or stabilizes the patient's BI-RADS® score one or more annual intervening mammographic detections.
  • the time period the one or more annual intervening mammographic detections may be 1 to 20 years, for example, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 6 years, 10 years, 15 years, or 20 years.
  • the time period the one or more annual intervening mammographic detections may be 1 year, 2 years, 4 years, 5 years, 7 years, 10 years, 15 years, or 20 years.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density of the patient's breast one or more annual intervening mammographic detections. In certain embodiments, the pharmaceutical formulation may be used to reduce or decrease the VBD % and/or AVBD of the patient's breast one or more annual intervening mammographic detections. In certain embodiments, the pharmaceutical formulation may be used to reduce or decrease the ABD % and/or AABD of the patient's breast between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density of the patient's breast in the range of between 1% to 99% between one or more annual intervening mammographic detections, such as, in the range of between 1% to 80%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 60%, 30% to 50%, or 30% to 40% between one or more annual intervening mammographic detections.
  • one or more annual intervening mammographic detections such as, in the range of between 1% to 80%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%
  • the pharmaceutical formulation may be used to reduce or decrease the VBD % and/or AVBD of the patient's breast in the range of between 1% to 99% between one or more annual intervening mammographic detections, such as, in the range of between 1% to 80%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 60%, 30% to 50%, or 30% to 40% between one or more annual intervening mammographic detections.
  • one or more annual intervening mammographic detections such as, in the range of between 1% to 80%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to
  • the pharmaceutical formulation may be used to reduce or decrease the ABD % and/or AABD of the patient's breast in the range of between 1% to 99% between one or more annual intervening mammographic detections, such as, in the range of between 1% to 80%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 60%, 30% to 50%, or 30% to 40% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density of the patient's breast by at least 2% between one or more annual intervening mammographic detections, such as, by at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 85%, 95%, or 99% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the VBD % and/or AVBD of the patient's breast by at least 2% between one or more annual intervening mammographic detections, such as, by at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 85%, 95%, or 99% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the ABD % and/or AABD of the patient's breast by at least 2% between one or more annual intervening mammographic detections, such as, by at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 85%, 95%, or 99% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to maintain or stabilize the mammographic breast density of the patient's breast between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density of the patient's breast by at least 2%, such as 5%, 10%, 20%, or 30%, over a 4 hour period, such as over an 8 hour, 24 hour, 1 day, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9 months, or 1 year period.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density VBD % and/or AVBD of the patient's breast by at least 2%, such as 5%, 10%, 20%, or 30%, over a 4 hour period, such as over an 8 hour, 24 hour, 1 day, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9 months, or 1 year period.
  • the pharmaceutical formulation may be used to reduce or decrease the mammographic breast density ABD % and/or AABD of the patient's breast by at least 2%, such as 5%, 10%, 20%, or 30%, over a 4 hour period, such as over an 8 hour, 24 hour, 1 day, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9 months, or 1 year period.
  • the pharmaceutical formulation may be used to mitigate or reduce the patient's risk of developing breast cancer.
  • the pharmaceutical formulation may be used to mitigate or reduce the patient's risk of developing breast cancer between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation may be used to mitigate or reduce the patient's risk of developing breast cancer and avoids, mitigates, reduces or reverses one or more peri-menopausal symptoms between one or more annual intervening mammographic detections.
  • the one or more peri-menopausal symptoms that may be mitigated, reduced, or avoided may include but is not limited to, menstrual irregularity; hot flashes and sleep problems; mood changes; mood swings; irritability; depression; vaginal dryness; urinary or vaginal infections; urinary incontinence; decreasing fertility; changes in sexual arousal or desire; bone loss; fragile bones; osteoporosis; or changing cholesterol levels, such as an increase in low-density lipoprotein (LDL) cholesterol, a decrease in high-density lipoprotein (HDL) cholesterol; or combinations thereof.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • the pharmaceutical formulations may be used to increase or improve the patient's fat to breast tissue ratio between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation increases or improves the patient's fat to breast tissue ratio from 1:19 to 19:1 between one or more annual intervening mammographic detections, such as increases or improves the treated patient's fat to breast tissue ratio from 1:15 to 19:1, from 1:10 to 19:1, from 1:5 to 19:1, from 1:2 to 19:1, from 2:3 to 19:1, from 2:1 to 19:1, from 4:1 to 19:1, from 6:1 to 19:1, from 8:1 to 19:1, from 10:1 to 19:1, from 1:19 to 10:1, from 1:10 to 10:1, from 1:4 to 10:1, from 1:2 to 10:1, from 3:2 to 10:1, from 3:1 to 10:1, from 5:1 to 10:1, from 7:1 to 10:1, from 9:1 to 10:1, from 15:1 to 10:1, from 1:15 to 5:1, from 1:5 to 5:1, from 1:5 to 5
  • the pharmaceutical formulation may be used to increase or improve the patient's fat to breast tissue ratio from 1:19 to 19:1, such as from 1:10 to 19:1, from 1:5 to 19:1, from 1:2 to 19:1, from 2:3 to 19:1, from 2:1 to 19:1, over a 4 hour period, over an 8 hour period, over a 24 hour period, over a 3 day period, over a 1 week period, over a 2 week period, over a 1 month period, over a 2 month period, over a 3 month period, over a 6 month period, over a 9 month period, over a 1 year period, or over a 5 year period.
  • 1:19 to 19:1 such as from 1:10 to 19:1, from 1:5 to 19:1, from 1:2 to 19:1, from 2:3 to 19:1, from 2:1 to 19:1, over a 4 hour period, over an 8 hour period, over a 24 hour period, over a 3 day period, over a 1 week period, over a 2 week period, over a 1 month period, over a 2 month period,
  • the pharmaceutical formulations may be used to increase the percentage of fat in the treated patient's breast between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation increases the percentage of fat in the treated patient's breast in the range of between 1% to 99% between one or more annual intervening mammographic detections, such as, in the range of between 1% to 90%, 1% to 70%, 1% to 50%, 1% to 30%, 1% to 20%, 1% to 15%, 1% to 10%, 3% to 60%, 3% to 20%, 5% to 70%, 5% to 50%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 50%, 20% to 30%, 30% to 60%, 30% to 50%, or 30% to 40% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation increases the percentage of fat in the treated patient's breast by at least 2%, such as by at least 5%, by at least 10%, by at least 25%, by at least 40%, by at least 75%, by at least 95%, or by at least 99%, over a 4 hour period, such as over an 8 hour period, over a 24 hour period, over a 3 day period, over a 1 week period, over a 2 week period, over a 1 month period, over a 2 month period, over a 3 month period, over a 6 month period, over a 9 month period, over a 1 year period, or over a 5 year period.
  • a 4 hour period such as over an 8 hour period, over a 24 hour period, over a 3 day period, over a 1 week period, over a 2 week period, over a 1 month period, over a 2 month period, over a 3 month period, over a 6 month period, over a 9 month period, over a 1 year period, or over a 5 year period.
  • the pharmaceutical formulation enhances, increases, or improves, breast compression during mammographic visualization or detection of the breast between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation enhances, increases, or improves, breast compression during mammographic visualization or detection of the breast in the range of between 5% to 70%, 5% to 50%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 70%, 30% to 50%, or between 30% to 40% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation further mitigates or reduces the patient's pain during the breast compression.
  • the pharmaceutical formulation further mitigates, reduces or minimizes, the patient's pain during the breast compression in the range of between 5% to 80%, 5% to 50%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40%, 10% to 20%, 10% to 15%, 20% to 70%, 20% to 50%, 20% to 30%, 30% to 70%, 30% to 50%, or between 30% to 40% less pain as a result of the enhanced, increased, or improved, breast compression during mammographic visualization or detection of the breast.
  • the pharmaceutical formulation mitigates or reduces the patient's pain during the breast compression.
  • the pharmaceutical formulation mitigates or reduces the patient's pain during the breast compression in the range of between 5% to 80%, 5% to 60%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 70%, 20% to 50%, 20% to 30%, 30% to 90%, 30% to 50%, or between 30% to 40% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation further enhances, increases, or improves, breast compression during mammographic visualization or detection of the breast between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation further enhances, increases, or improves, breast compression during mammographic visualization or detection of the breast between one or more annual intervening mammographic detections in the range of between 5% to 80%, 5% to 60%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40%, 10% to 20%, 10% to 15%, 20% to 80%, 20% to 60%, 20% to 30%, 30% to 80%, 30% to 50%, or between 30% to 40% between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation mitigates or reduces the patient's pain according to the visual analog scale (VAS) during the breast compression.
  • VAS visual analog scale
  • the pharmaceutical formulation mitigates or reduces the patient's pain according to the VAS during the breast compression such that the patient does not suffer from significant pain between 50-100 mm, 50-80 mm, 50-70 mm, 60-100 mm, 70-100 mm, 80-100 mm or between 90-100 mm during one or more mammographic detections or during one or more annual intervening mammographic detections.
  • the pharmaceutical formulation enhances increases or improves the patient's compliance of having regular mammographic visualizations or detections, for example, compliance with mammographic visualizations or detections at every 6 months, annually, every 2 years, every 3 years, or every 5 years.
  • the pharmaceutical formulation mitigates or reduces the amount of radiation exposure required to visualize or detect the patient's breast during one or more subsequent mammographies, such as during one or more subsequent annual mammographies.
  • the pharmaceutical formulation mitigates or reduces the amount of radiation exposure required to visualize or detect the patient's breast in the range of between 5% to 99%, 5% to 80%, 5% to 70%, 5% to 50%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40%, 10% to 20%, 10% to 15%, 20% to 80%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 80%, 30% to 60%, 30% to 50% or between 30% to 40% during one or more subsequent mammographies, such as during one or more subsequent annual mammographies.
  • the pharmaceutical formulation induces breast involution in the breast of the patient, for example, in the breast of a peri-menopausal patient.
  • the pharmaceutical formulation induces involution of breast cells in the breast of the patient, for example, in the breast of a peri-menopausal patient.
  • the pharmaceutical formulation induces net cell death over proliferation in the breast of the patient, for example, in the breast of a peri-menopausal patient.
  • the pharmaceutical formulation reverses cell number and mammographic breast density in the breast of the patient, for example, in the breast of a peri-menopausal patient.
  • the pharmaceutical formulation mitigates or reduces breast stiffness in the breast of the patient, for example, in the breast of a peri-menopausal patient.
  • the pharmaceutical formulation mitigates or reduces breast stiffness in the breast of the patient in the range of between 5% to 80%, 5% to 60%, 5% to 40%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 80%, 20% to 60%, 20% to 40%, 20% to 30%, 30% to 80%, 30% to 60%, or between 30% to 40%, between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation mitigates or reduces breast stiffness in the breast of the patient by at least 5%, such as at least 8%, at least 10%, at least 15%, at least 20%, or at least 30%, per annum.
  • the pharmaceutical formulation mitigates or reduces breast stiffness in the breast of the patient by at least 5%, such as at least 8%, at least 10%, at least 15%, at least 20%, or at least 30%, over a 4 hour period, such as over an 8 hour period, a 24 hour period, a 3 day period, a 1 week period, a 2 week period, a 1 month period, a 2 month period, a 3 month period, a 6 month period, a 9 month period, a 1 year period, or a 5 year period.
  • the pharmaceutical formulation enhances, increases, or improves mammographic visualization or detection of the breast of the patient, for example, the breast of a peri-menopausal patient.
  • the pharmaceutical formulation enhances, increases, or improves mammographic visualization or detection of the breast of the patient in the range of between 5% to 80%, 5% to 50%, 5% to 30%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 80%, 20% to 60%, 20% to 30%, 30% to 80%, 30% to 60%, or between 30% to 40%, between one or more annual intervening mammographic detections.
  • the pharmaceutical formulation enhances, increases, or improves mammographic visualization or detection of the breast of the patient by at least 5%, such as at least 10%, at least 15%, at least 25%, at least 40%, at least 50%, or at least 75%, over a 4 hour period, or over other time periods, such 8 hours, 24 hours, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9 months, 1 year, or 5 years.
  • the pharmaceutical formulation reduces mammographic breast density and avoids inducing masculinizing androgenic side-effects or inducing a hyper-androgenic state.
  • masculinizing androgenic side-effects may include male-type baldness, hirsutism, or increased hair in areas unwanted by the patient, voice deepening, acne, or combinations thereof.
  • the pharmaceutical formulation reduces mammographic breast density and is exclusive of inducing masculinizing androgenic side-effects or inducing a hyper-androgenic state.
  • the pharmaceutical formulation reduces mammographic breast density and minimizes induction of masculinizing androgenic side-effects or induction of a hyper-androgenic state.
  • the pharmaceutical formulation substantially improves or improves the patient's physical functioning, such as physical functioning related to the patient's central nervous system, libido, musculoskeletal system, cardiovascular system, risk of contracting autoimmune diseases, the severity of symptoms associated with autoimmune disease, or combinations thereof.
  • the pharmaceutical formulation may reduce depression, anxiety, general cognitive dysfunction including memory, or reduce the risk of dementia and Parkinsonism.
  • the pharmaceutical formulation may provide a significant improvement in global libido, including speed to sexual arousal and the ability to achieve orgasm.
  • the pharmaceutical formulation may provide for a reduction in inflammatory and degenerative arthritis, an improvement in bone mineral density, or an improvement in muscle strength.
  • the pharmaceutical formulation may provide a reduction in foamy macrophage deposition in the arterial wall, a reduction in atherosclerosis, an increase in high density lipoprotein's leading to an improvement in cholesterol, or a high-density lipoprotein ratio.
  • the pharmaceutical formulation may substantially reduce or reduces the treated patient's risk of contracting autoimmune diseases, such as Sjogren's syndrome, lupus, and rheumatoid arthritis.
  • the pharmaceutical formulation may substantially reduce or reduces the severity of symptoms associated with a treated patient's autoimmune disease, such as Sjogren's syndrome, lupus, and rheumatoid arthritis.
  • the pharmaceutical formulation substantially improves or improves the patient's physical functioning, such as cognitive function; reduction of a degenerative CNS disease, comprising dementia or parkinsonism; muscle strength; libido; energy; reduction of monoamine oxidase induced anxiety and depression; or combinations thereof.
  • the pharmaceutical formulation further provides one or more of the following: i) reduces mammographic breast density; ii) increases involutionary effects on the patient's breast without conversion of testosterone to estrogen; iii) substantially reduces, reduces, or reverses peri-menopausal symptoms; or iv) substantially improves or improves the patient's physical functioning, comprising cognitive function; reduction of symptoms associated with a degenerative CNS disease, comprising dementia or parkinsonism; muscle strength; libido; energy; reduction of monoamine oxidase induced anxiety and depression; or combinations thereof.
  • the pharmaceutical formulation further provides one or more of the following: i) reduces mammographic breast density; ii) increases involutionary effects on hormonally affected end organs, comprising breast, without conversion of testosterone to estrogen; iii) substantially reduces, reduces, or reverses peri-menopausal symptoms related to fluctuating estrogen levels; or iv) substantially improves or improves the patient's physical functioning, comprising cognitive function; reduction of symptoms associated with a degenerative CNS disease, comprising dementia or parkinsonism; muscle strength; libido; energy; reduction of monoamine oxidase induced anxiety and depression; or combinations thereof.
  • the patient has a high free androgenic index level, for example, 30% or greater, within their breast within four hours of the administration of the androgenic agent and the aromatase inhibitor. In certain embodiments, the patient has a supra-physiological free androgenic index level within their breast within four hours of the administration of the androgenic agent and the aromatase inhibitor.
  • the treatment with a pharmaceutical formulation or combination treatment of the androgenic agent and the aromatase inhibitor as described herein further comprises: a) measuring free androgenic index levels and/or aromatase inhibitor levels in serum isolated from a blood sample taken from the patient after at least 1 month of treatment; b) determining a subsequent dose, comprising a subsequent effective amount of androgenic agent and a subsequent effective amount of an aromatase inhibitor, and c) administering to the patient the subsequent dose.
  • the treatment with a pharmaceutical formulation or combination treatment of the androgenic agent and the aromatase inhibitor as described herein further comprises: a) measuring free androgenic index levels and/or aromatase inhibitor levels in serum isolated from a blood sample taken from the patient after at least 1 month of treatment, comprising centrifuging the patient's blood sample to isolate the serum; b) determining a subsequent dose, comprising a subsequent effective amount of androgenic agent and a subsequent effective amount of an aromatase inhibitor, and c) administering to the patient the subsequent dose.
  • the measured free androgenic index serum levels of a treated patient after 1 month may be between 10-25%, such as between 10-20%, 10-15%, 15-25%, 15-20%, 12-18%, 8-15%, or between 11-14%.
  • the measured free androgenic index serum levels of a treated patient after 3 months may be between 2-10%, such as between 2-8%, 2-6%, 2-5%, 2-4%, 4-10%, 5-8%, 3-7%, 4-6%, 3-6%, 4-7%, 5-10% or between 2-5%.
  • the administration of the aromatase inhibitor reduces aromatization of testosterone to estrogen in the subcutaneous fat of the treated patient, for example, reduces aromatization by 80-95% or 100%.
  • the administered aromatase inhibitor may reduce aromatization of testosterone to estrogen in the subcutaneous fat of the patient's breast, the subcutaneous fat of the patient's pelvis, the subcutaneous fat of the patient's buttocks, the subcutaneous fat of the patient's abdomen or combinations thereof, for example, reduces aromatization by 80-95% or 100%.
  • the administration of the aromatase inhibitor reduces aromatization of adrenal androgens, for example, androstenedione, to estrogen in the subcutaneous fat of the treated patient, for example, reduces aromatization by 80-95% or 100%.
  • the administered aromatase inhibitor may reduce aromatization of testosterone to estrogen in the subcutaneous fat of the patient's breast, the subcutaneous fat of the patient's pelvis, the subcutaneous fat of the patient's buttocks, the subcutaneous fat of the patient's abdomen or combinations thereof, for example, reduces aromatization by 80-95% or 100%.
  • Annual mammographic screening of density may be undertaken to determine the reduction in breast density utilizing an appropriate mammographic algorithm that measures the volume of fibro-glandular tissue as a percentage of total breast volume (MBD).
  • MBD volume of fibro-glandular tissue as a percentage of total breast volume
  • the objective is to achieve MBD of less than 10% when this is a function of the average of both breast densities.
  • the rate of breast density reduction should be at least 2% per annum.
  • An annual uplift factor (V1(N) in the above) may be introduced into TD and AD of 10% of dosing if 2% is not achieved in the first year. This annual uplift factor typically will only be introduced, on an annual basis, if there is less than 10% increase in androgenicity index (AI).
  • VBD % volume of fibro-glandular tissue as a percentage of total breast volume
  • the objective is to achieve VBD % of less than 10% when this is a function of the average of both breast densities.
  • the rate of breast density reduction (VBD %) should be at least 2% per annum.
  • An annual uplift factor (V1(N) in the above) may be introduced into TD and AD of 10% of dosing if 2% is not achieved in the first year. This annual uplift factor typically will only be introduced, on an annual basis, if there is less than 10% increase in androgenicity index (AI).
  • the administration of aromatase inhibitor in combination with testosterone results in an improvement in the bioavailability of dihydrotestosterone between 25% to 75%, 35% to 65% or 45% to 55%.
  • the amount of increase in bioavailability of dihydrotestosterone is greater than 25%, greater than 35%, greater than 45% or greater than 55%.
  • the androgenic agent used in a pharmaceutical formulation or combination treatment as described herein may be selected from the group consisting of testosterone, methyltestosterone, and/or dehydroepiandrosterone.
  • the androgenic agent may be testosterone undecanoate, such as about 40 mg of testosterone undecanoate.
  • the aromatase inhibitor for example, may be selected from the group consisting of anastrozole, exemestane, or letrozole. In certain aspects, the aromatase inhibitor may be anastrozole, such as about 1 mg of anastrozole.
  • the pharmaceutical formulation may include administering a pharmaceutical formulation comprising an androgenic agent linked to an aromatase inhibitor, e.g., via an ester linkage, or an androgenic agent/aromatase inhibitor complex, wherein the complex is created by methods in the art.
  • both the androgenic agent e.g., testosterone, methyltestosterone, and/or dehydroepiandrosterone
  • the aromatase inhibitor e.g., anastrozole, exemestane, or letrozole
  • the androgenic agent e.g., testosterone, methyltestosterone, and/or dehydroepiandrosterone
  • the aromatase inhibitor e.g., anastrozole, exemestane, or letrozole
  • the androgenic agent e.g., testosterone, methyltestosterone, and/or dehydroepiandrosterone
  • the aromatase inhibitor e.g., anastrozole, exemestane, or letrozole
  • testosterone and anastrozole may be administered subcutaneously.
  • the appropriate dosing regimen utilizing the androgenic agent, the aromatase inhibitor, or pharmaceutical formulations comprising the androgenic agent and the aromatase inhibitor, the amount of each dose administered, and the intervals between doses of the compounds may depend on various factors such as the particular aromatase inhibitor and androgenic agent being used in combination, the type of pharmaceutical formulation being used, the type of physiological condition being treated, the characteristics of the subject being treated (e.g., species, age, weight, sex, medical condition, fed/fasted), the route of administration, and the severity of the disorder being treated or combinations thereof.
  • a physician or diagnostician of ordinary skill may readily determine and prescribe the effective amount of the androgenic agent, the aromatase inhibitor, or pharmaceutical formulation to prevent or to treat the specific physiological condition.
  • the pharmaceutical formulation or formulation to be administered may contain a quantity of the compounds or pharmaceutically acceptable salts or esters thereof in an amount effective to treat the condition of the subject being treated. Because two different compounds may be used together in a combination therapy, the potency of each of the compounds and the interactive effects achieved by combining them together typically will also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amounts needed to improve side effects.
  • Administration of the androgenic agent and the aromatase inhibitor, or the pharmaceutical formulation comprising a combination of the same, to the subject includes both self-administration and administration to the subject by another person (e.g., physician, nurse, health care worker, friend, etc.).
  • the pharmaceutical formulation may be formulated in a manner compatible with a desired outcome.
  • the pharmaceutical formulations may be administered in a convenient formulation.
  • the following formulation examples only are illustrative and are not intended to limit the scope of the present disclosure.
  • the pharmaceutical formulation can be an implant or pellet formulated by direct compression.
  • the pellet formulations may incorporate diluents, binders, lubricants and, disintegrators as well as the active ingredients.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, and/or polyvinylpyrrolidine. Polyethylene glycol, ethyl cellulose and waxes may also serve as binders.
  • a lubricant may be necessary for a pellet formulation to prevent the pellet and punches from sticking in the die.
  • the lubricant may be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and/or hydrogenated vegetable oils.
  • the implant or pellet will have an implant or pellet hardness in a range of from about 6 Kg/N to about 10 Kg/N, preferably from about 7 Kg/N to about 9 Kg/N, most preferable about 8 Kg/N and all such dosage forms within this range are expressly provided for herein.
  • a sustained release multi-phasic concentration pattern as described herein may be obtained. Knowing that such a release pattern of an androgenic agent and aromatase inhibitor may be obtained, a person of ordinary skill in the art will be able to utilise different ingredients in the formulation in view of the disclosures provided herein and provide such pharmaceutical formulations in accordance with the present disclosure.
  • the implant or pellet may be inserted into the subcutaneous fat of the subject's pelvis, the subcutaneous fat of the subject's breast, the subcutaneous fat of the subject's buttocks, the subcutaneous fat of the subject's abdomen or combinations thereof.
  • the implant or pellet may be inserted into the subcutaneous fat of the subject's lower abdominal wall.
  • the implant or pellet may be inserted into the subcutaneous fat of the subject's upper gluteal region.
  • the androgenic agent and aromatase inhibitor may be provided in pharmaceutical formulations other than for subcutaneous administration either together in the same formulation or in separate formulations for use in combination treatments as described herein, such formulations comprising one or more of suitable filler(s), lubricants, binders, disintegrants and/or pharmaceutically acceptable carriers or excipients as described above or used in the provision of pharmaceutical formulations for the desired route of administration and/or for obtaining the desired release pattern (e.g., a sustained release multi-phasic release pattern) of the active(s).
  • suitable filler(s), lubricants, binders, disintegrants and/or pharmaceutically acceptable carriers or excipients as described above or used in the provision of pharmaceutical formulations for the desired route of administration and/or for obtaining the desired release pattern (e.g., a sustained release multi-phasic release pattern) of the active(s).
  • kits may additionally include instructions for using the kit components in one or more of the disclosed methods. Instructions may include instructions for practicing one or more of the disclosed methods.
  • a kit may include an androgenic agent or an aromatase inhibitor in a pharmaceutical formulation in a container, pack, or dispenser together with instructions for administration to a human subject. Instructions may additionally include indications of a satisfactory clinical endpoint or any adverse symptoms that may occur or any additional information required by the Food and Drug Administration for use in humans.
  • the instructions may be on “printed matter,” e.g., on paper or cardboard within the kit, or on a label affixed to the kit or packaging material, or attached to a vial or tube containing a component of the kit. Instructions may additionally be included on a computer readable medium, such as a disk (floppy diskette or hard disk), optical CD such as CD- or DVD-ROM/RAM, magnetic tape, electrical storage media such as RAM and ROM, and hybrids of these such as magnetic/optical storage media.
  • a computer readable medium such as a disk (floppy diskette or hard disk), optical CD such as CD- or DVD-ROM/RAM, magnetic tape, electrical storage media such as RAM and ROM, and hybrids of these such as magnetic/optical storage media.
  • Example 1 A Single Dose Trial to Evaluate the Pharmacokinetics of Testosterone and Anastrozole from a Subcutaneous Testosterone and Anastrozole Implant, 80 mg/4 mg (T+Ai) in Women
  • Pellets for subcutaneous insertion were prepared by compressing sterile non-micronized testosterone, anastrozole and stearic acid in an 80:4:2 ratio into a 5 mm diameter cylindrical die. The pellets are transferred to a sterile 5 ml amber vial covered with sterile cotton wool and sealed with a rubber stopper and aluminium rip seal which is crimped. The vials are sterilized by gamma irradiation at 25 KGy. Testosterone non-micronized and anastrozole, USP grade, were obtained from Azelis (Brookvale, NSW). The stearic acid, NF quality, was obtained from Medisca (Mascot, NSW). The steps for producing these pellets are outlined below:
  • MBD Mammographic Breast Density
  • PK pharmacokinetic
  • BMI Body Mass Index
  • the objective of this therapy is to reduce aromatisation of T at the insertion site (i.e., subcutaneous adipose where the aromatase level is average and in tissues where the aromatase is high) the minimal effective dose is given compared to when treating breast cancer where total body aromatase inhibition is sought to maximise anti-neoplastic effect.
  • the IC50 for anastrozole in tissue overexpressing aromatase is 3.62 and 5.66 nM respectively.
  • This example provides an analysis of the used testosterone and anastrozole combination therapy for mammographic breast density (MBD) reduction in woman.
  • MBD mammographic breast density
  • the study was conducted at the Wellend Clinic (Burnside War Memorial Hospital, Sydney, South Australia).
  • the major indication for therapeutic intervention was one or more of the following: perimenopausal hormone dysfunction, high MBD, which is considered a factor in reducing breast cancer (BC) risk.
  • All 652 patients were female, with an average age at the time of first T+Ai implant of 52 years (ranging from 23 to 79 years).
  • Reduction of MBD/BC risk was the primary indication for treatment in 89 patients (14%), assistance with hormonal dysfunction in 334 patients (51%) and both indications in 177 patients (27%). The primary indication was not provided for 52 patients.
  • BC Crohn's disease
  • model statement represents an item from the previous bullet list.
  • the random statement is used to account for repeated measurements taken over time within each patient.
  • An unstructured covariance structure was used as it provided a slightly better fit when compared to compound symmetry (CS) and autoregressive (AR1) options in SAS®.
  • LSMEANS and LSMESTIMATE statements were used to estimate the change from baseline in MBD by testosterone dose strata, at 1-year, 2-years, and 3-years. Table 3 presents parameter estimates obtained from the model.
  • the PK and PD of anastrozole shown in Example 1 shows that a larger dose of anastrozole (4 mg per implant) may be used that achieves efficacy and also avoids, or minimizes, side effects associated with the aromatase inhibitors disclosed herein.
  • This example provides an analysis of a pharmacokinetic profile of anastrozole using a modelling approach in order to evaluate an optimal input function to describe absorption of the trial set forth in Example 1.
  • Table 6 sets forth the sampling schedule for anastrozole and testosterone. Blood samples of at least 8 mL were collected for serum testosterone/DHT and plasma anastrozole by venipuncture at each time point specified in table 6.
  • FIGS. 7 A-B illustrate the anastrozole absorption rates. Data in these figures are presented as mean+/ ⁇ standard deviation.
  • FIG. 7 A shows the Y axis on the log scale.
  • FIG. 7 B shows the Y axis on a linear scale. The figures were produced using the pellet absorption data summarized in Table 2 of Example 1.
  • FIGS. 8 A-B plot the plasma anastrozole concentration post implantation.
  • the data on the X axis is plotted in time (hours) after transplantation.
  • the X axis is on a log scale.
  • the open circles equal observed data
  • the black line equals median PK profile
  • the dashed dark grey line equals lower limit of quantification (0.1 ng/mL).
  • FIG. 9 shows the frequency of observation post implantation. Approximately fifteen percent of the data was below the lower limit of quantification (BLQ). The BLQ concentrations were observed either pre-dose or after 1000 hours post implantation.
  • FIG. 10 shows a flow chart of the models tested.
  • FIG. 11 shows the final structure model used in this example.
  • BSV body-subject variability
  • KA apparent volume of distribution for the central compartment
  • KA first-order absorption rate constant
  • a proportional error model was used to describe residual unexplained variability (RUV).
  • FIGS. 12 A-B shows the population and individual predictions.
  • FIG. 12 A shows the population prediction.
  • FIG. 12 B shows the individual prediction.
  • the light grey lines represent the line of identity and the dark grey lines show the trend in the data (Loess smooth). The tailing in the trend line for FIG. 12 B is expected since the BLQ data are censored.
  • Overall the model predicts the data well with minimal bias.
  • Population predicted concentration is the representation of a typical patient.
  • the individual predicted concentration is a post-Bayes/individualized prediction.
  • FIG. 13 (ID:1-11) shows the individual plots of observed and predicted plasma concentrations of anastrozole. The data was plotted at nominal times.
  • the dashed black lines equal population model prediction, the solid grey lines equals individual model prediction, and the circles equals individual observed data.
  • the final model was used to simulate 1000 replicates of the dataset to validate the model simulation characteristics. From the simulated data, the 95% CI around the median, and 10 th and 90 th prediction intervals were calculated. The median, 10 th and 90 th percentiles of the observed data was then overlaid on the simulated data to validate the model.
  • FIG. 14 shows a visual predictive check (VPC) of anastrozole concentration post implantation.
  • VPC visual predictive check
  • the VPC shows that the observed data was captured well by the simulated data from the model.
  • FIGS. 15 A-B shows one versus two compartment model.
  • FIG. 15 A represents a one compartment disposition with first order.
  • FIG. 15 B represents a two-compartment disposition with a dual input.
  • the distribution of conditional weighted residuals (CWRES) against time for the one compartment model ( FIG. 15 A ) shows that there was a misspecification in the elimination phase.
  • the two-compartment model shows the CWRES distribution over time is evenly distributed.
  • FIG. 16 displays predictions for patient 10 from several different input models including: A single first order input (Model 9), a simultaneous first and zero order input (Model 10), a single zero order input (Model 11) and a dual first order input (Model 15 1). From the plots it was evident that models other than the dual first order input fails to properly capture the early phase of absorption.
  • anastrozole PK follows a two-compartment disposition profile.
  • the absorption profile of anastrozole was well described by a dual input.
  • the other input models failed to properly capture the absorption phase.
  • This example looks at the potential effect on breast tissue elasticity as assessed by shear wave ultrasound in the subjects that took part in the trial set forth in Example 1.
  • Breast elasticity was measured by shear wave ultrasound measure on Days 1, 29, 57 and 85.
  • Four measurements of glandular tissue elasticity and fatty tissue elasticity were taken for each breast.
  • the calculated average of the eight measurements for each tissue type was the value used in summaries and analyses of breast elasticity.
  • a summary of breast elasticity at each timepoint, and of the change from baseline is provided in table 8.
  • Table 8 demonstrated breast tissue elasticity reduced progressively over time, with reductions from baseline of 28% for glandular tissues and 32% for fatty tissue.
  • the breast tissue of women with autoimmune inflammatory mastitis is high in aromatase and estradiol and thus Treg expression are heavily suppressed.
  • Induction of CD36 in the breast tissue of women with AIM may result in tissue specific immunosuppression without systemic immunosuppression.
  • This example shows that CD36 can be expressed in normal breast tissue by treatment with an androgenic agent in combination with an aromatase inhibitor as described herein.
  • Normal breast tissue was excised from 3 peri-menopausal women taken during surgery.
  • the tissue samples were transported to the laboratory on ice, with a maximum time of one hour between excision and tissue processing.
  • the breast tissue samples were washed in media (phenol red-free RPMI; SAFC biosciences, Kansas, USA), supplemented with 5 ml of 200 mM glutamine (SAFC biosciences, Kansas, USA), 5 ml of 100 ⁇ anti-biotic/anti-mycotic (Sigma, St Louis, Mo., USA), 10 ⁇ g/ml insulin (Sigma, St Louis, Mo., USA), and 10 ⁇ g/ml hydrocortisone (Sigma, St Louis, Mo., USA) to remove excess blood.
  • media phenol red-free RPMI; SAFC biosciences, Kansas, USA
  • 5 ml of 100 ⁇ anti-biotic/anti-mycotic Sigma, St Louis, Mo., USA
  • 10 ⁇ g/ml insulin Sigma, St Louis, Mo., USA
  • a representative piece of each tissue sample was immediately fixed in 4% formalin in phosphate-buffered saline (PBS) overnight at 4° C., followed by dehydration using an automatic tissue processor (Sakura Tissue-Tek VIP, USA) and paraffin wax embedding.
  • a haematoxylin and eosin (H&E) stained section was used to assess tissue pathology.
  • the remaining fresh tissue was cut into small ( ⁇ 3 ⁇ 3 ⁇ 1 mm) pieces, and placed as triplicates on 1 cm 3 gelatin sponges (Spongostan; Johnson & Johnson, Skipton, UK) that were pre-soaked and then half submerged in treatment media containing 10% dextran-coated charcoal stripped fetal calf serum (DCC-FCS) (SAFC biosciences, Kansas, USA) in 24-well tissue culture plates (BD Biosciences, NJ, USA). The tissues samples were then cultured for 24 hours in a vehicle of 0.1% ethanol, 5 nM of testosterone and 25 ng/ml of anastrozole.
  • DCC-FCS dextran-coated charcoal stripped fetal calf serum
  • Western blotting whole cell lysates of and control adipose tissue were prepared by sonication at 48 C in lysis buffer (1% Triton X-100, 50 mM KCl, 25 mM HEPES, pH 7.8, 10 mg/ml of leupeptin, 20 mg/ml of aprotinin, 125 mM dithiothreitol and 1 mM phenylmethylsulfonyl fluoride) and analyzed on the same western blot.
  • lysis buffer 1% Triton X-100, 50 mM KCl, 25 mM HEPES, pH 7.8, 10 mg/ml of leupeptin, 20 mg/ml of aprotinin, 125 mM dithiothreitol and 1 mM phenylmethylsulfonyl fluoride
  • the band density was measured by densitometry, using Image Master VDS and Image Quant Analysis Software (Amersham Pharmacia Biotech, Hong Kong).
  • the relative protein levels of CD36 and beta-actin in the original total protein lysate from the breast preparations were obtained.
  • CD36 protein expression was normalized to beta-actin protein expression.
  • Immunizing host produced the antibodies with a synthetic peptide derived from the sequence of human CD36, purified by peptide affinity chromatography and confirmed using control peptides.
  • Increasing CD36 increases conversion of fibroblasts to adipocytes (fat).
  • the adipocytes (fat) is a semi-fluid and therefore has greater elasticity.
  • the present example shows a significant increase in CD36 in normal breast tissue following treatment with the androgenic agent testosterone in combination with the aromatase inhibitor anastrozole. Increased CD36 expression is associated with a reduction in breast stiffness.
  • certain embodiments of the present disclosure are directed to use of a combination therapy of an androgenic agent and an aromatase inhibitor to increase CD36 and a reduction in breast stiffness.
  • the patient had a bra cup size of 32A, and was unable to wear a bra post-morbid.
  • VAS pain scale pre-morbid 95 mm
  • FIG. 19 A Mammograms of a breast of the patient before and after treatment are shown in FIG. 19 A , and MRI images before treatment for the subsequent 3 years following treatment are shown in FIG. 19 C .
  • FIG. 19 B Breast volume and density measurements are shown in FIG. 19 B .
  • the patient had a bra cup size of 36C and was unable to wear bra post morbid-she wore a sports bra all day and to bed.
  • VAS pain scale pre-morbid 100 mm
  • Subcutaneous implant pellet of 80 mg Testosterone and 4 mg anastrozole for 3 months, repeated for two further 3 month period.
  • FIG. 20 A Mammograms of a breast of the patient before and after treatment are shown in FIG. 20 A .
  • Breast volume and density measurements are shown in FIG. 20 B .
  • Pre-morbid 34C unable to wear bra post morbid-worn sports bra all day and to bed.
  • VAS pain scale pre-morbid 100 mm
  • FIG. 21 A Mammograms of a breast of the patient before and after treatment are shown in FIG. 21 A .
  • Breast volume and density measurements are shown in FIG. 21 B .
  • Kevlar protective kit A 41 year old police officer with rapid breast enlargement—“very hard”, diffuse inflammation and severe constant pain over 1 month which was unresponsive to over the counter analgesia and NSAIDs impacting on the patients work and home life-could not wear Kevlar protective kit.
  • VAS pain scale pre-morbid 100 mm
  • FIG. 22 A MRI images of a breast of the patient before and after treatment are shown in FIG. 22 A , and mammographic images before and after treatment are shown in FIG. 22 B .
  • FIG. 22 C Breast volume and density measurements are shown in FIG. 22 C .
  • Pre-morbid 36B enlarged to 36EE.
  • Obstetric/Gynological history included an irregular 28 day cycle—amenorrhoeic due to Zoladex, with no pregnancies. No abnormalities in blood parameters were noted.
  • VAS pain scale pre-morbid 100 mm
  • FIG. 23 A A mammographic image of a breast of the patient before treatment is shown in FIG. 23 A .
  • An MRI image after the treatment is shown in FIG. 23 B .
  • Plasma cell mastitis is an autoimmune inflammatory destructive process of the retro-areolar milk ducts which results in multiple fistulae and inevitably results in disfiguring surgery and a high risk of recurrence. There is no known treatment for this condition apart from surgery which has significant limitations. Plasma cell mastitis is exemplified by the invasion of the milk duct system with inflammatory cells that secrete pro-inflammatory cytokines. Recently it has been demonstrated that the IL-6 inflammatory pathways critical in this inflammatory process and has been targeted as a potential mechanism to be targeted for treatment of plasma cell mastitis (Liu, 2020). It has been demonstrated that the female breast has cells which are extremely responsive (a reduction of 53%) to treatment with testosterone in reducing IL-6 levels (Guhl, 2012).
  • Granulomatous mastitis is also known as granulomatous lobular mastitis due to the inflammation occurring around the breast lobules. It is a manifestation of autoimmune inflammatory mastitis in the breast tissue which results in granuloma formation, inflammation and fistula formation. There is no known cure for this condition and women frequently undergo multiple operations and/or receive immunosuppressive treatment.
  • FIG. 24 A A mammographic image of a breast of the patient before treatment is shown in FIG. 24 A .
  • An MRI image obtained after treatment is shown in FIG. 23 B .
  • a pharmaceutical formulation comprising:
  • the formulation upon administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • the pharmaceutical formulation is compressed into a pellet
  • the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • the formulation upon administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • the pharmaceutical formulation is compressed into a pellet
  • the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern in the serum or plasma of the subject comprising:
  • the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.25 mm to 4.75 mm and a length of between 4 mm to 7 mm;
  • the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern comprising:
  • the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.25 mm to 4.75 mm and a length of between 4 mm to 7 mm;
  • the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the aromatase inhibitor;
  • the sustained release multi-phasic concentration pattern comprising:
  • a pharmaceutical formulation comprising:
  • the pharmaceutical formulation is compressed into a pellet that has a diameter of between 4.4 mm to 4.6 mm and a length of between 4 mm to 7 mm;
  • the pellet upon subcutaneous administration to a subject provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the testosterone or an ester thereof, and plasma concentration for the anastrozole;
  • the sustained release multi-phasic concentration pattern comprising:

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